Abstract
Human noroviruses (HuNoVs) are responsible for more than 95% of the non-bacterial acute gastroenteritis epidemics in the world. The CDC estimates that every year 21 million individuals suffer from HuNoV-induced gastroenteritis in the United States. Currently, there is no FDA-approved vaccine for HuNoVs. Development of an effective vaccine has been hampered by the lack of an efficient cell culture system for HuNoVs and a suitable small animal model for pathogenesis study. In this study, we developed lactic acid bacteria (LAB) as a vector to deliver HuNoV antigen. A LAB strain (Lactococcus lactis) carrying VP1 gene of a HuNoV GII.4 virus (LAB-VP1) was constructed. It was found that HuNoV VP1 protein was highly expressed by LAB vector and was secreted into media supernatants. To test whether LAB-based HuNoV vaccine candidate is immunogenic, 4-day-old gnotobiotic piglets were orally inoculated with various doses of LAB-VP1. It was found that LABs were persistent in the small intestine of piglets and shed in pig feces for at least 25 days post inoculation. LAB DNA and VP1 were detected in mesenteric lymph nodes and spleen tissue in LAB-VP1 inoculated groups. HuNoV-specific IgG and IgA were detectable in serum and feces respectively at day 13 post-inoculation, and further increased at later time points. After being challenged with HuNoV GII.4 strain, a large amount of HuNoV antigens were observed in the duodenum, jejunum, and ileum sections of the intestine in the LAB control group. In contrast, significantly less, or no, HuNoV antigens were detected in the LAB-VP1 immunized groups. Collectively, these results demonstrate that a LAB-based HuNoV vaccine induces protective immunity in gnotobiotic piglets.
Highlights
We developed a lactic acid bacteria (LAB)-based Human noroviruses (HuNoVs) vaccine candidate
HuNoV strain was cloned into a LAB expression vector pNZ8150, which was subsequently transformed into Lactococcus lactis by electroporation, resulting in a LAB bacteria strain expressing
HuNoV GII.4 strain 766 was amplified by room temperature (RT)-PCR and cloned into the LAB expression vector pNZ8150, which was subsequently transformed into Lactococcus lactis by electroporation, resulting in LAB bacteria strains designated “LAB-VP1.”
Summary
Human norovirus (HuNoV) is the causative agent of more than 95% of nonbacterial acute gastroenteritis cases worldwide [1]. HuNoV is responsible for over 60% of foodborne illnesses in the United States. It is estimated that 21 million people are infected by HuNoV, which result in approximately 800 deaths annually in the United States. HuNoV causes a global economic burden, with $60.3 billion in healthcare costs on a yearly basis [2,3]. HuNoV is highly infectious and contagious, and approximately ten virus particles are sufficient to establish an infection [4,5].
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